Uric acid‐dependent inhibition of AMP kinase induces hepatic glucose production in diabetes and starvation: evolutionary implications of the uricase loss in hominids

Abstract

Reduced AMP kinase (AMPK) activity has been shown to play a key deleterious role in increased hepatic gluconeogenesis in diabetes, but the mechanism whereby this occurs remains unclear. In this article, we document that another AMP-dependent enzyme, AMP deaminase (AMPD) is activated in the liver of diabetic mice, which parallels with a significant reduction in AMPK activity and a significant increase in intracellular glucose accumulation in human HepG2 cells. AMPD activation is induced by a reduction in intracellular phosphate levels, which is characteristic of insulin resistance and diabetic states. Increased gluconeogenesis is mediated by reduced TORC2 phosphorylation at Ser171 by AMPK in these cells, as well as by the up-regulation of the rate-limiting enzymes PEPCK and G6Pc. The mechanism whereby AMPD controls AMPK activation depends on the production of a specific AMP downstream metabolite through AMPD, uric acid. In this regard, humans have higher uric acid levels than most mammals due to a mutation in uricase, the enzyme involved in uric acid degradation in most mammals, that developed during a period of famine in Europe 1.5 × 10(7) yr ago. Here, working with resurrected ancestral uricases obtained from early hominids, we show that their expression on HepG2 cells is enough to blunt gluconeogenesis in parallel with an up-regulation of AMPK activity. These studies identify a key role AMPD and uric acid in mediating hepatic gluconeogenesis in the diabetic state, via a mechanism involving AMPK down-regulation and overexpression of PEPCK and G6Pc. The uricase mutation in the Miocene likely provided a survival advantage to help maintain glucose levels under conditions of near starvation, but today likely has a role in the pathogenesis of diabetes.

Ketohexokinase C blockade ameliorates fructose-induced metabolic dysfunction in fructose-sensitive mice

“…To examine gluconeogenesis, we evaluated the expression levels of PEPCK and G6Pase, which are known as good indicators of gluconeogenesis (31). However, in opposition to our initial hypothTo better understand the mechanism whereby hepatic triglyceride accumulation occurs in aldolase B-deficient mice chronically exposed to fructose, we analyzed the expression of enzymes Figure 1).…”

High fructose diet feeding accelerates diabetic nephropathy in Spontaneously Diabetic Torii (SDT) rats

“…In our study, urinary uric acid excretion in the SDT rats fed high fructose diet was higher than that in the SDT rats fed basal diet and was much higher than that in the high fructose-fed SD rats. It's known that AMP deaminase activity in the liver is higher in diabetic animals (Cicerchi et al, 2014). The differences in the response of urinary uric acid levels between the high fructose-fed SDT rats and the high fructose-fed SD rats were considered to be related to higher AMP deaminase activity in the SDT rats.…”

Metabolic and Kidney Diseases in the Setting of Climate Change, Water Shortage, and Survival Factors

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